Basic–liver, pancreas, and biliary tractGlucagon-Like Peptide-1 and Its Receptor Agonist Exendin-4 Modulate Cholangiocyte Adaptive Response to Cholestasis
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Materials
Reagents were purchased from Sigma Chemical (St. Louis, MO) unless otherwise indicated. Intracellular cyclic adenosine 3′, 5′-monophosphate (cAMP) and D-myo-Inositol 1,4,5-triphosphate (IP3) levels were determined with RIA kits purchased from Amersham (Arlington Heights, IL). Antibodies for immunoblotting were purchased from Santa Cruz Biotechnologies Inc. (Santa Cruz, CA), unless differently indicated. The antibody anti-GLP1R was purchased by Alpha Diagnostic (San Antonio, TX); the antibody
Cholangiocytes Express the GLP-1R, That Is, Up-regulated in the Course of Cholestasis
Both RT-PCR and immunoblots show the presence of GLP-1R in cholangiocytes (Figure 1). Interestingly, the quantitative analysis of the immunoblotting data demonstrate that GLP-1R expression is up-regulated after 1-week BDL (Figure 1, right panel). The semiquantitative evaluation of GLP-1 mRNA expression confirms such changes in mRNA expression (Figure 1, left panel).
GLP-1R Activation Stimulates Cholangiocyte Proliferation In Vitro
The in vitro incubation of normal rat cholangiocytes with increasing doses of GLP-1 determined a progressive increase in cell
Discussion
The current study provides evidence that GLP-1 is a potent stimulator of cholangiocyte proliferation, and that it is required for the proliferative response of the biliary epithelium to cholestasis. In particular, this study shows that: (1) cholangiocytes express the GLP-1R that is up-regulated in the course of cholestasis; (2) activation of the GLP-1R by GLP-1 or by the selective agonist exendin-4 stimulates normal rat cholangiocyte proliferation; (3) these changes in cell growth are mediated
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The authors of this manuscript declare no conflict of interest to disclose.
Supported by MIUR Grant 2005067975_004 to Dr. Marzioni and by the Università Politecnica delle Marche Intramural Grants ATBEN00205 to Dr. Benedetti and ATMAR01105 to Dr. Marzioni; a VA Merit Award, a VA Research Scholar Award, the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White to Dr. Alpini, and the NIH Grant DK062975 to Dr. Alpini.